Immunocompetent mouse models revealed that S100A4⁺ monocytes/macrophages facilitate long-term Zika virus infection in the testes

ABSTRACT

During its global epidemic, Zika virus (ZIKV) attracted widespread attention due to its link with various severe neurological symptoms and potential harm to male fertility. However, the understanding of how ZIKV invades and persists in the male reproductive system is limited due to the lack of immunocompetent small animal models. In this study, immunocompetent murine models were generated by using anti-IFNAR antibody blocked C57BL/6 male mice and human STAT2 (hSTAT2) knock in (KI) male mice. After infection, viral RNA could persist in the testes even after the disappearance of viremia. We also found a population of ZIKV-susceptible S100A4⁺ monocytes/macrophages that were recruited into testes from peripheral blood and played a crucial role for ZIKV infection in the testis. By using single-cell RNA sequencing, we also proved that S100A4⁺ monocytes/macrophages had a great impact on the microenvironment of ZIKV-infected testes, thus promoting ZIKV-induced testicular lesions. In conclusion, this study proposed a novel mechanism of long-term ZIKV infection in the male reproductive system.

KEYWORDS:

• ZIKV
• mouse models
• human STAT2 KI mice
• S100A4
• testis

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

W. Yang and C. Zhang performed experiments and analyzed the data. L.B. Liu and Z.Z. Bian performed animal experiments. J.T. Chang and D.Y. Fan helped to maintain cells, viruses, J. An, P.G. Wang and N. Gao conceived the project, analyzed the data, wrote and reviewed the manuscript. J. An coordinated the whole research.

Additional information

Funding

We appreciate the grants from the National Key Research and Development Plan of China (2021YFC2300202 to J.A.), The National Natural Science Foundation of China (U1902210 to J.A., 82372251 to P.G.W., 81871641 to P.G.W., 81972979 to J.A., and 82172266 to P.G.W.) and Natural Science Foundation of Beijing (7232002 to N.G.). The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.